Diabetes mellitus is a familial disease with a heterogeneous expression that includes immunologic as well as metabolic, renal, neurologic and vascular features. The long term objectives of our overall research program are to provide insights into the manifestations of this disease. The aims of this proposal are to delineate those immunologic and genetic components that may contribute to the pathogenesis of insulin-dependent diabetes mellitus (IDDM). The goals are to characterize prospectively the immune responses of patients with IDDM to human or pork insulins to ascertain if these immune responses are controlled by immune response (Ir) genes associated with or linked to the major histocompatibility complex (MHC) or other genetic markers. Besides measuring total insulin bound antibody, we will measure isotypic IgE, IgG and IgM antibodies to insulin along with lymphocyte proliferation responses to insulin. Those immune responses to insulin which may be detected at the time of diagnosis and before insulin treatment is instituted will be compared to the presence of islet cell antibodies. These immune responses will be compared to HLA-DR types, immunoglobulin allotypes (Gm and Km), Kidd blood and DNA restriction fragment length polymorphism. The possibility that there is impaired production of antibodies and cellular immune responses following immunization with influenza vaccine in patients with IDDM will be explored in a pilot study. Whether these immune responses to influenza vaccine in IDDM patients may be associated or linked to the MHC or other genetic markers will also be investigated. The subjects with IDDM to be studied will be recruited from the Pittsburgh IDDM Registry. This is one of the most extensive and complete registries of IDDM in the world with over 100 multiplex families with IDDM within the context of over 1,200 families evaluated. This well defined cohort of IDDM patients provide an exceptional opportunity to study prospectively the immunologic responses of these patients and their families as related to the development of IDDM.